Deposition products, composite materials and processes for the production thereof

ABSTRACT

A composite material comprising a substrate and a deposition product and the use of a deposition product for providing an antimicrobial effect. The substrate of the composite material is a medical device. Further, in each of the composite material and the use, the deposition product consists essentially of at least one oxidized silver species and wherein the deposition product is comprised of a compound having the formula Ag 7 O 8 X, where X is an anion.

This Application is a Continuation of U.S. application Ser. No.11/934,459 filed on Nov. 2, 2007 (which issued on Mar. 30, 2010 as U.S.Pat. No. 7,687,076), which is a Continuation of U.S. application Ser.No. 10/830,574 filed on Apr. 23, 2004 (which issued on Nov. 27, 2007 asU.S. Pat. No. 7,300,673).

FIELD OF INVENTION

Deposition products, composite materials including deposition products,and methods for producing the deposition products and the compositematerials.

BACKGROUND ART

The germicidal properties of silver, even not known as such, have beenutilized since the early Mediterranean cultures. It has been known since1000 BC and possibly before that water kept in silver vessels and thenexposed to light and filtered could be rendered potable. Other forms ofsilver have been used throughout centuries for various applications,such as coatings for prevention of beverages from spoilage or silverplates and foils in the surgical treatments of wounds and broken bones.

The lethal effects of metals towards bacteria and lower life forms werefirst scientifically described by von Nageli in the late nineteenthcentury, and this phenomenon has been defined as an “oligodynamiceffect” (N. R. Thompson, Silver, in Comprehensive Inorganic Chemistry,Vol. III D, J. C. Bailer, H. J. Emeléus, R. Nyholm and A. F.Trutman-Dickenson, Editors, Pergamon Press, Oxford (1973)). The termoligodynamic effect is typically restricted to describing solutions inwhich the metal concentration is several orders of magnitude lower thanthat which would be lethal to higher organisms.

The investigation of the bacteriostatic properties of pure metals suchas Fe, Mo, Cu, V, Sn, W, Au, Al, Ta, Nb, Ti, Zr, Ni, Co, Ag and Cr, hasproved that Co was the only element which was inhibitory for thebacterial growth under anaerobic conditions (K. J. Bundy, M. F. Butlerand R. F. Hochman, “An Investigation of the Bacteriostatic Properties ofPure Metals”, Journal of Biomedical Materials Research, Vol. 14 (1980)653-663). Under aerobic conditions both Cu and Co consistently displayinhibitory effects. Some antimicrobial effects have been seen for Ni, Feand V. However, other metals such as Mo, W, Al, Nb, Zr, Cr and mostimportantly for the present invention Ag and Sn never showed anytendency to inhibit the growth of Streptococcus mutans.

In the case of silver metal, it was in 1920, when Acél who was the firstto attribute the antimicrobial properties of silver to the liberation ofAg⁺ ions from the material (D. Acél, “Über die oligodynamische Wirkungder Metalle”, Z. Biochem., 112 (1920) 23).

Gibbard reported in 1937 that pure metallic silver has no antimicrobialactivity (J. Gibbard, “Public Health Aspects of the Treatment of Waterand Beverages with Silver”, Journal of American Public Health, Vol. 27(1937) 112-119). His experiments showed that if silver is cleanedmechanically with an abrasive cloth or paper it becomes inactive.Similarly, if molten silver is allowed to cool in a reduction atmosphere(e.g. hydrogen), no antimicrobial activity is found. When cooling ofmolten silver is carried out in air, and formation of surface oxideoccurred, an antimicrobial activity may be observed. Similar resultswere found when silver metal was treated with nitric acid in an airatmosphere (dissolution and formation of an oxide layer). Based onGibbard's results, pure silver was devoid of activity, but surfaceoxidized silver was active. Silver oxide, silver nitrate and silverchloride were always active. Also, Gibbard observed that theantimicrobial properties of silver and its compounds were reduced in thepresence of proteins or glucose.

Djokić investigated the behavior of silver films, e.g. physical vapordeposited, electrodeposited, electroless deposited and metallurgical inphysiological saline solutions (S. S. Djokić and R. E. Burrell,“Behavior of Silver in Physiological Solutions”, Journal of theElectrochemical Society, Vol. 145 (5) (1998) 1426-1430). Djokić foundthat an essential factor leading to an antimicrobial activity ofmetallic silver is a presence of Ag oxide(s) at the surface of thismaterial. It was demonstrated that only silver films containing silveroxides (most likely Ag₂O) showed an antimicrobial activity. The behaviorwas attributed to the dissolution of Ag₂O from the “silver” material andformation of Ag⁺ or other complexed ions which become antimicrobiallyactive. There was no evidence that pure metallic silver, no matter whichway it was produced i.e., physical vapor deposited, electrodeposited orelectroless deposited could be dissolved in physiological media, or thatthese materials would exhibit antimicrobial activity.

It should be noted that when the physical vapor deposition of silver wascarried out in an atmosphere containing oxygen the resulted product, asfound by the XRD analysis contained silver oxide. Consequently, thesesamples exhibited antimicrobial activity. Conversely, when the physicalvapor deposition was carried out from an argon atmosphere (no presenceof oxygen) pure metallic, nanocrystalline silver film was deposited asconfirmed by the XRD analysis. However, these films did not dissolve inphysiological saline solutions, nor they exhibited antimicrobialactivity at all.

For an in depth understanding of structural properties of silver filmsproduced by reactive sputtering, see Djokić et al. (S. S. Djokić, R. E.Burrell, N. Le and D. J. Field, “An Electrochemical Analysis of ThinSilver Produced by Reactive Sputtering”, Journal of the ElectrochemicalSociety, Vol. 148 (3) (2001) C191-C196.). To prove the concept that onlyoxidized silver species are responsible for the antimicrobial activity,Djokić further oxidized pure metallic silver samples (i.e. thoseproduced by the electrodeposition, electroless deposition, physicalvapor deposition in an argon atmosphere or metallurgically). Theoxidation of these samples was carried out electrochemically in 1 M KOHsolutions, using a process very well established in the art. Theelectrochemically oxidized silver samples were tested for theantimicrobial activity against Pseudomonas Aeruginosa. Clear evidencewas found that the electrochemically oxidized silver samples exhibitedantimicrobial activity.

The above referenced work shows that only oxidized silver species, butnot elemental silver will affect antimicrobial activity. The findings todate show that the “nanocrystalline” or “macrocrystalline” elementalsilver does not have antimicrobial activity at all. Elemental silver,either nanocrystalline or “macrocrystalline” may exhibit someantimicrobial activity only if oxidized silver species are present atthese surfaces or within the silver metal. Only the formation of silveroxide(s), carbonates or other silver salts (except silver sulfide, dueto its extremely low solubility) at the surface or within the material,which may be influenced by an exposure of elemental silver to variousbases, acids or due to atmospheric corrosion may lead to anantimicrobial activity of this material.

The use of silver on chronic wounds dates back in the 17^(th) and18^(th) centuries. In the early 19^(th) century, silver nitrate began tobe used on burns and in opthalmology. Concentrations of the solutionranged from 0.20 to 2.5 wt. % with the weaker solutions being reservedfor children. Silver has been found to be active against a wide range ofbacterial, fungal and viral pathogens. Topical treatment of acute andchronic wounds is a preferred and selective approach to the preventionof infection and healing. In order to achieve these requirementsproducts that are used in the prevention of infections must have certainphysical and chemical properties.

When used for topical dressings, silver compounds must have relativelylow solubility. This is usually achieved by choosing compounds with arelatively low solubility products (e.g. AgCl, Ag₂SO₄, Ag₂CO₃, Ag₃PO₄,Ag-oxides). Kinetics of dissolution of these compounds in neutralaqueous solutions is quite slow. This property is very convenient fortwo reasons. First, a sustained release of silver ions from the silvercompounds is more likely to provide a prolonged antimicrobial activity.Second, low amounts of the silver ions released into wound exudates maynot give rise to transient high tissue blood and urine levels, thusavoiding systemic toxicity. The choice of a particular silver compoundwill depend upon its reactivity with wound exudates. This reactivityshould preferably be minimized in order to achieve the desired effect ofthe released silver ions (i.e., antimicrobial activity without systemictoxicity).

Besides silver nitrate, one of the most widely used topicalantimicrobial materials is silver sulfadiazine (C. L. Fox, “TopicalTherapy and the development of Silver Sulfadiazine”, Surgery, Gynecology& Obstetrics, 157 (1) (1983) 82-88). This compound is synthesized fromsilver nitrate and sodium sulfadiazine. Silver sulfadiazine has beenused in treatments of burns, leg ulcers and also as a topicalantimicrobial agent in the management of infected wounds.

Products such as silver protein (argyrols) or mild silver protein aremixtures of silver nitrate, sodium hydroxide and gelatin. These productsare recommended for internal use and are promoted as essential mineralsupplements. Although there is no theoretical or practical justificationfor their use, this class of compounds has been recommended for thetreatment of diverse diseases such as cancer, diabetes, AIDS and herpes(M. C. Fung, D. L. Bowen, “Silver Products for Medical Indications:Risk—Benefit Assessment”, Clinical Toxicology, Vol. 34 (1) (1996)119-126).

Silver-zinc-allantoinate has been formulated as a cream and represents acombination of silver, zinc and allantoin (an agent that stimulatesdebridement and tissue growth (H. W. Margaf, T. H. Covey, “A Trial ofSilver-Zinc-Allantoinate in the Treatment of Leg Ulcers”, Arch. Surg.,Vol. 112 (1977) 699-704). This composition exhibited promising effectsin preliminary studies.

In the past few decades several topical dressings containing silver havebeen developed for wound care. Such materials include Arglaes™,Silverlon™, Acticoat™, Actisorb™, and Silver 220™.

Antimicrobial coatings and methods of forming same are the subject ofU.S. Pat. No. 5,681,575 (Burrell et al) and U.S. Pat. No. 6,238,686(Burrell et al). The coatings are formed by the physical vapordeposition of biocompatible metal and the preferred biocompatible metalis silver.

Burrell et al teach that atomic disorder may be created in metal powdersor foils by cold working and in metal coatings by depositing by vapordeposition at low substrate temperatures and that such metal coatingsconstitute a matrix containing atoms or molecules of a differentmaterial. The presence of different atoms or molecules results in atomicdisorder in the metal matrix, for instance due to different sized atoms.The different atoms or molecules may be one or more second metals, metalalloys or metal compounds which are co- or sequentially deposited withthe first metal or metals to be released. Alternatively, the differentatoms or molecules may be adsorbed or trapped from the working gasatmosphere during reactive vapor deposition.

In U.S. Pat. No. 6,238,686 Burrell et al claim a modified materialcomprising one or more metals in a form characterized by sufficientatomic disorder such that the material, in contact with a solvent forthe material, releases atoms, ions, molecules or clusters containing atleast one metal at an enhanced rate relative to its normal orderedcrystalline structure. In U.S. Pat. No. 5,681,575 Burrell et al claim amedical device which includes a coating of one or more anti-microbialmetals having a “sufficient atomic disorder”.

It is unclear from either U.S. Pat. Nos. 5,681,575 or 6,238,686 whatwould constitute a material characterized by “sufficient atomicdisorder”. In nature, most materials would exhibit sufficient atomicdisorder if the true atomic disorder described (by drawings or mapping)in ordinary Chemistry or Physics handbooks were insufficiently ordered(with a regular geometric structure or like).

In any event, the teachings of Burrell et al appear to connect “atomicdisorder” with an “enhanced rate” of release of “atoms, ions, moleculesor clusters”. If the term “release” further relates to a dissolution (asdefined in textbooks of General Chemistry and Physics), then thisdissolution should lead to the liberation of ions or molecules insolvent. When released in the solvent, these ions or molecules areusually solvated i.e. surrounded by the molecules of the solvent. It isvery unlikely that atoms of a metal will be released into a solutioncomprising of water such as in the wound environment. If released intosolution in its elemental state, metals would rather represent arelatively larger particles comprising of more than one or a few atoms.

As a result, the term “atom” as used in Burrell et al is not exactlydescriptive. It is not known yet scientifically whether atoms of metalscan be released into aqueous solutions at pH close to neutral (e.g., pHrange 6 to 8), except in the case of colloidal solutions which areusually prepared by adequate chemical reactions in-situ.

U.S. Pat. No. 6,087,549 (Flick) discloses a multilayer laminate wounddressing comprising a plurality of layers of a fibrous material, witheach layer comprising a unique ratio of metalized fibers to nonmetalizedfibers. In a preferred embodiment the wound dressing consists of threelayers and the metal is silver. The wound contact layer has the highestratio of metalized fibers to nonmetalized fibers, the intermediate layerhas a lower ratio of metalized fibers to nonmetalized fibers, and theouter layer has the lowest ratio of metalized fibers to nonmetalizedfibers. The wound dressing described by Flick is commercially availableunder the trade-mark Silverlon™.

U.S. Pat. No. 5,211,855 (Antelman), U.S. Pat. No. 5,676,977 (Antelman)and U.S. Pat. No. 6,436,420 (Antelman) teach that tetrasilver tetroxide(Ag₄O₄) containing two monovalent and two trivalent silver ions exhibitsbactericidal, fungicidal and algicidal properties. As a result,“tetrasilver tetroxide” is suggested for use for water treatment in U.S.Pat. No. 5,211,855 and for use in destroying the AIDS virus in U.S. Pat.No. 5,676,977.

In U.S. Pat. No. 6,436,420, Antelman describes a method of deposition orinterstitial precipitation of tetrasilver tetroxide (Ag₄O₄) crystalswithin the interstices of fibers, yarns and/or fabrics forming sucharticles in order to produce fibrous textile articles possessingenhanced antimicrobial properties. The interstitial precipitation ofAg₄O₄ is achieved by immersion of the article to be treated (e.g.,fiber, yarn or fabric) in an aqueous solution containing a water solublesilver salt, most preferably silver nitrate. After uniformly wetting thearticle, the article is removed into a second heated aqueous solution(having a temperature of at least 85 degrees Celsius or more preferablyat least 90 degrees Celsius) containing strong alkali (most preferablyNaOH) and a water soluble oxidizing agent (most preferably potassiumpersulfate) for 30 seconds to 5 minutes to facilitate the precipitationof tetrasilver tetroxide.

After the reaction is completed, the article is removed and washed. Thearticle treated in this way is described as exhibiting outstandingantimicrobial resistance towards pathogens such as bacteria, viruses,yeast and algae. The article is also described as being resistant toultraviolet light and as maintaining its antimicrobial properties aftera number of launderings.

SUMMARY OF INVENTION

The present invention is directed at deposition products, compositematerials and at methods for the production of deposition products andcomposite materials. The deposition products are comprised of at leastone oxidized species of a metal.

The methods of the invention are based upon chemical depositionprinciples and techniques. The methods of the invention may be carriedout under either acidic or alkaline conditions. The methods of theinvention may comprise the step of exposing ions of the metal to anoxidizing agent to produce the deposition product. The methods of theinvention may involve the production of the deposition product itself orthe production of a composite material which comprises a substrate andthe deposition product.

The methods of the invention are particularly suited for producing acomposite material which is comprised of a substrate and a very thincoating or deposition layer of the deposition product. This thin coatingor layer may be in the order of one or several atoms in thickness, whichfacilitates the production of a composite material which has arelatively high surface area to volume ratio. The coating may also bedeposited so that it does not completely cover the substrate, thusleaving portions of the surface of the substrate uncoated. Compositematerials produced using the methods of the invention may be useful fora variety of applications, including but not limited to electronics,materials engineering and medical applications.

The methods of the invention may be carried out at relatively lowtemperatures. Preferably the methods of the invention are carried out attemperatures of no greater than about 60 degrees Celsius. Morepreferably the methods of the invention are carried out at roomtemperature (i.e., between about 10 degrees Celsius and about 25 degreesCelsius).

The metal and the oxidizing agent are selected so that they arecompatible with the production of the desired deposition product. As aresult, any suitable metal and any suitable oxidizing agent may be usedin the invention. The metal may also be comprised of more than oneelement, with the result that the deposition product may be comprised ofat least one oxidized species of more than one metal element.

Preferably the metal is comprised of silver and the deposition productis comprised of at least one oxidized species comprising silver. Themetal may, however, be further comprised of other metal elements such asgold, copper, tin or zinc so that the deposition product is comprised ofat least one oxidized species comprising silver and one or more othermetals.

Where the metal is comprised of silver, the resulting deposition productmay exhibit significant antimicrobial properties. Without intending tobe limited by theory, it is believed that these antimicrobial propertiesare due to the presence in the deposition product of one or moreoxidized silver species. The presence of other metals in the depositionproduct may enhance these antimicrobial properties or may provide othercomplementary properties to the deposition product.

More particularly, it is believed that silver containing depositionproducts produced using the methods of the invention may be comprised ofsilver ions having valent states higher than one, such as for example Ag(II) and Ag (III) valent states. It is also believed that silvercontaining deposition products produced using the methods of theinvention may be comprised of silver ions having more than one valentstate so that the oxidized silver species may be comprised of amultivalent substance. Finally, it is believed that silver containingdeposition products produced using the methods of the invention may becomprised of a silver containing substance or a plurality of silvercontaining substances which react over time to form other silvercontaining substances which may exhibit differing antimicrobialproperties. It is believed that if this is the case, the depositionproducts produced by the invention may be useful for providing a variedantimicrobial response and for overcoming bacterial resistance.

In particular, in certain aspects, the methods of the invention may beused to produce a deposition product which comprises a substance havingthe general formula Ag₇O₈X, where X is an anion. The deposition productmay be further comprised of Ag₂SO₄. The deposition product may also becomprised of other oxidized silver compounds such as one or more silveroxides selected from the group of silver oxides consisting of monovalentsilver oxide, bivalent silver oxide, trivalent silver oxide and mixturesthereof.

The anion X may be comprised of a single anion or may be comprised of aplurality of different anions. The anion may therefore be comprised ofany anion or combination of ions. The anion may, for example, beselected from the group of anions consisting of HCO₃ ⁻, CO₃ ²⁻, NO₃ ⁻,ClO₄ ⁻, SO₄ ²⁻, F⁻, and mixtures thereof. The source of the anion may bea metal compound which provides the ions of the metal. For example,where the deposition solution is comprised of a silver salt such assilver nitrate, the anion may be comprised of the nitrate ion (NO₃ ⁻).An alternative or secondary source of the anion X may optionally beprovided in order to provide sufficient quantities of the anion forproduction of the deposition product. Where an alternative or secondarysource of the anion X is provided, the source of anions may be comprisedof any source, including but not limited to any organic or inorganicacid.

Where the metal is comprised of silver, the composite materials producedby the methods may therefore be useful as medical devices or ascomponents of medical devices due to their specific antimicrobialproperties. These composite materials may also provide other advantages.As one example, the ability to provide a very thin coating or layer ofthe deposition product on the substrate makes it possible to minimizethe amount of silver which must be used in the composite material inorder to provide a desired antimicrobial response. As a second example,the ability to provide a very thin coating or layer of the depositionproduct on the substrate minimizes the extent to which the depositionproduct will interfere with the properties and functions of thesubstrate, particularly if the deposition product is deposited on thesubstrate so that it does not completely cover the surface of thesubstrate. This second example may be particularly significant where thesubstrate is comprised of an adhesive material such as a skin adhesivelayer.

In a first aspect, the invention is a method for producing a compositematerial comprising a substrate and a deposition product, wherein thedeposition product is comprised of at least one oxidized species of ametal, the method comprising the following steps:

-   -   (a) first contacting the substrate with a first basic        environment comprising ions of the metal in order to expose the        substrate to the ions of the metal; and    -   (b) second contacting the substrate with a second basic        environment in order to produce the composite material.

The first basic environment may be comprised of any environment in whichmetal ions are present under alkali conditions. The metal may becomprised of any metal or combinations of metals but preferably themetal is comprised of silver.

Preferably the first basic environment is comprised of a first basicsolution comprising an amount of a silver diamino complex. Morepreferably, the first basic solution results from a mixture of a silvercompound and ammonium hydroxide in an aqueous medium. Preferably thesilver compound is selected from the group of silver compoundsconsisting of silver salts, silver oxides and mixtures thereof. Morepreferably the silver compound is comprised of silver nitrate.

The first basic solution may have any alkaline pH. Preferably the firstbasic solution has a pH in the range from about 8 to about 14. Withinthese parameters, the amount of ammonium hydroxide in the first basicsolution is preferably selected such that a concentration of ammoniumhydroxide in the first basic solution is between about 25 percent andabout 35 percent by volume of the first basic solution. Preferably theamount of silver compound in the first basic solution is selected suchthat a concentration of the silver compound in the first basic solutionis between about 1 gram per liter and about 20 grams per liter.

The second basic environment may be comprised of any environment havingalkali conditions. Preferably the second basic environment is a stronglyalkaline environment having a pH at least about 12. Preferably thesecond basic environment is comprised of a second basic solutioncontaining an amount of a strong alkali compound. The strong alkalicompound may be comprised of any compound which can provide the strongalkaline environment. For example, the strong alkali compound may becomprised of one or more Group I elements, including lithium, sodium,potassium, rubidium, cesium and francium. Preferably the strong alkalicompound is selected from the group of compounds consisting of sodiumhydroxide and potassium hydroxide and mixtures thereof and morepreferably the strong alkali compound is comprised of sodium hydroxide.Preferably the amount of hydroxide compound in the second basic solutionis selected such that a concentration of the hydroxide compound in thesecond basic solution is between about 15 grams per liter and about 35grams per liter.

The first contacting step may be performed for any length of time whichis sufficient to expose the substrate to the ions of the metal.Preferably the substrate is substantially completely exposed to the ionsof the metal. Preferably the first contacting step is performed forbetween about 1 minute and about 10 minutes.

The second contacting step may be performed for any length of time whichis sufficient to cause the production of the deposition product.Preferably the second contacting step is performed for a sufficient timein order to maximize the yield of the deposition product. Preferably thesecond contacting step is performed for between about 1 minute and about60 minutes.

The first contacting step may be performed at any temperature. Thesecond contacting step may be performed at any temperature. Preferably,however, the second contacting step is performed at a temperature ofbetween about 2 degrees Celsius and about 60 degrees Celsius.

The method according to the first aspect may be further comprised of thestep of washing the composite material following the second contactingstep.

The method according to the first aspect may be further comprised of thestep of adding an amount of an oxidizing agent to the second basicenvironment during the second contacting step. The oxidizing agent maybe comprised of any oxidizing agent which is compatible with the metal,but the oxidizing agent is preferably selected from the group ofoxidizing agents consisting of persulfates, permanganates, peroxides andmixtures thereof. More preferably the oxidizing agent is comprised of apersulfate. The persulfate may be comprised of any persulfate butpreferably the persulfate is selected from the group of persulfatesconsisting of potassium persulfate, sodium persulfate, ammoniumpersulfate and mixtures thereof. More preferably the persulfate iscomprised of ammonium persulfate, potassium persulfate or mixturesthereof, and most preferably the persulfate is comprised of potassiumpersulfate.

The amount of the oxidizing agent is preferably selected to becompatible with the amount of the ions of the metal so that thedeposition product can be produced as efficiently as possible. In otherwords, the amount of the oxidizing agent is preferably selected to be astoichiometrically appropriate amount relative to the amount of the ionsof the metal. Preferably the amount of persulfate oxidizing agent isselected such that a concentration of the persulfate in the second basicsolution is between about 1 gram per liter and about 25 grams per liter.

The method according to the first aspect may be further comprised of thestep, prior to the first contacting step, of etching the substrate byimmersing the substrate in an etching solution in order to prepare thesubstrate for the deposition product. The etching step may involveeither or both of a physical process or a chemical process. The etchingstep preferably prepares the substrate for the deposition product byincreasing the roughness of the substrate surface and/or creatingattraction sites for adsorption and/or deposition of the depositionproduct.

Any etching solution may be utilized which is suitable for a particularsubstrate. For example, where the substrate is comprised of an organicmaterial or polymer such as polyethylene, the etching solution ispreferably comprised of a mixture of an alcohol and an aqueous solutionof a hydroxide compound. The hydroxide compound may be comprised of anyhydroxide compound but is preferably selected from the group ofhydroxide compounds consisting of sodium hydroxide, potassium hydroxideand mixtures thereof. More preferably the hydroxide compound iscomprised of sodium hydroxide. The etching step may be performed for anylength of time sufficient to prepare the substrate, but preferably theetching step is performed for less than about 20 minutes and preferablyis performed for at least 5 minutes.

The method according to the first aspect may be further comprised of thestep of adding a residual silver compound to the second basicenvironment during the second contacting step. The residual silvercompound may be comprised of any suitable source of silver ions, butpreferably the residual silver compound is comprised of silver nitrate.Preferably the amount of residual silver compound is selected such thata concentration of the residual silver compound in the second basicsolution is between about 1 gram per liter and about 5 grams per liter.

The method according to the first aspect may be further comprised of thestep of agitating the second basic environment during at least a portionof the second contacting step in order to enhance the production of thedeposition product and the composite material.

In a second aspect, the invention is a method for producing a depositionproduct, wherein the deposition product is comprised of at least oneoxidized species of a metal, the method comprising the following steps:

-   -   (a) providing a deposition solution comprising an amount of ions        of the metal and an amount of an oxidizing agent; and    -   (b) producing the deposition product by facilitating a chemical        reaction in the deposition solution between the ions of the        metal and the oxidizing agent.

The metal may be comprised of any metal or combinations of metals butpreferably the metal is comprised of silver so that the ions of themetal are comprised of silver ions. The deposition solution may becomprised of silver ions from any source or in any form but preferablythe deposition solution is comprised of an aqueous solution of a silversalt. More preferably the silver salt is comprised of silver nitrate.

The ions of the metal may be present in any concentration. Preferably,where the ions of the metal are comprised of silver ions, the amount ofthe silver ions is selected so that a concentration of the silver saltin the deposition solution is between about 1 gram per liter and about20 grams per liter.

The oxidizing agent may be comprised of any oxidizing agent which iscompatible with the metal, but the oxidizing agent is preferablyselected from the group of oxidizing agents consisting of persulfates,permanganates, peroxides and mixtures thereof. More preferably theoxidizing agent is comprised of a persulfate. The persulfate may becomprised of any persulfate but preferably the persulfate is selectedfrom the group of persulfates consisting of potassium persulfate, sodiumpersulfate, ammonium persulfate and mixtures thereof. More preferablythe persulfate is comprised of ammonium persulfate, potassium persulfateor mixtures thereof, and most preferably the persulfate is comprised ofpotassium persulfate.

The amount of the oxidizing agent is preferably selected to becompatible with the amount of the ions of the metal so that thedeposition product can be produced as efficiently as possible. In otherwords, the amount of the oxidizing agent is preferably selected to be astoichiometrically appropriate amount relative to the amount of the ionsof the metal. For example, where the metal is comprised of silvernitrate the amount of silver nitrate is preferably selected such that aconcentration of the silver nitrate in the deposition solution isbetween about 1 gram per liter and about 20 grams per liter, in whichcase the amount of the oxidizing agent is preferably selected so that aconcentration of the oxidizing agent in the deposition solution isbetween about 1 gram per liter and about 50 grams per liter.

The method according to the second aspect may be used to produce adeposition product which comprises a substance having the generalformula Ag₇O₈X, where X is an anion. The deposition product may befurther comprised of Ag₂SO₄. The deposition product may also becomprised of other oxidized silver compounds such as one or more silveroxides selected from the group of silver oxides consisting of monovalentsilver oxide, bivalent silver oxide, trivalent silver oxide and mixturesthereof.

The anion X may be comprised of a single anion or may be comprised of aplurality of different anions. The anion may therefore be comprised ofany anion or combination of ions. The anion may, for example, beselected from the group of anions consisting of HCO₃ ⁻, CO₃ ²⁻, NO₃ ⁻,ClO₄ ⁻, SO₄ ²⁻, F⁻, and mixtures thereof. The source of the anion may bea metal compound which provides the ions of the metal. For example,where the deposition solution is comprised of a silver salt such assilver nitrate, the anion may be comprised of the nitrate ion (NO₃ ⁻).An alternative or secondary source of the anion X may optionally beprovided in order to provide sufficient quantities of the anion forproduction of the deposition product.

As a result, in the method according to the second aspect, the methodmay be further comprised of the step of adding a source of anions to thedeposition solution. The source of anions may be comprised of one ormore acids. The acid may be comprised of any organic or inorganic acid.For example, the acid may be selected from the group of acids consistingof carbonic acid, nitric acid, perchloric acid, sulfuric acid, aceticacid, fluoroboric acid, phosphoric acid, phosphorous acid, citric acid,acetylsalicylic acid and mixtures thereof. The amount of the source ofanions which is added to the deposition solution preferably is an amountwhich is selected to be compatible with the amount of the ions of themetal. In other words, the amount of the source of anions is preferablyselected to be a stoichiometrically appropriate amount relative to theamount of the ions of the metal.

The deposition product producing step is preferably performed at arelatively low temperature, since the deposition product may experienceincreasing solubility with increasing temperature. The depositionproduct producing step is preferably performed at a temperature ofbetween about 2 degrees Celsius and about 60 degrees Celsius, morepreferably at a temperature of between about 2 degrees Celsius and about40 degrees Celsius, and even more preferably at a temperature of betweenabout 10 degrees Celsius and about 25 degrees Celsius.

Preferably the deposition solution is agitated during at least a portionof the deposition product producing step in order to enhance theproduction of the deposition product.

The method according to the second aspect may be used to produce thedeposition product as a product, or may be used to produce a compositematerial comprising a substrate and the deposition product. Where themethod is used to produce a composite material, the method may befurther comprised of the following steps:

-   -   (a) providing a substrate; and    -   (b) contacting the substrate with the deposition solution during        the deposition product producing step, thereby producing a        composite material comprising the substrate and the deposition        product.

The substrate contacting step may be performed for any length of timewhich is sufficient to produce the composite material having a desiredcomposition. The substrate contacting step is preferably performed forat least about 1 minute, more preferably for between about 1 minute andabout 60 minutes, even more preferably for between about 1 minute andabout 20 minutes, and even more preferably for between about 2 minutesand about 10 minutes.

The method in the second aspect may be further comprised of the step,following the substrate contacting step, of washing the compositematerial.

The method according to the second aspect may be further comprised ofthe step, prior to the substrate contacting step, of etching thesubstrate by immersing the substrate in an etching solution in order toprepare the substrate for the deposition product. The etching step mayinvolve either or both of a physical process or a chemical process. Theetching step preferably prepares the substrate for the depositionproduct by increasing the roughness of the substrate surface and/orcreating attraction sites for adsorption and/or deposition of thedeposition product.

Any etching solution may be utilized which is suitable for a particularsubstrate. For example, where the substrate is comprised of an organicmaterial or polymer such as polyethylene, the etching solution ispreferably comprised of a mixture of an alcohol and an aqueous solutionof a hydroxide compound. The hydroxide compound may be comprised of anyhydroxide compound but is preferably selected from the group ofhydroxide compounds consisting of sodium hydroxide, potassium hydroxideand mixtures thereof. More preferably the hydroxide compound iscomprised of sodium hydroxide. The etching step may be performed for anylength of time sufficient to prepare the substrate, but preferably theetching step is performed for less than about 20 minutes and preferablyis performed for at least 5 minutes. Where the etching step isperformed, the method according to the second aspect preferably furthercomprises the step, following the etching step, of washing the substrateto remove residual alkali from the substrate.

The method according to the second aspect may be further comprised ofthe step, following the substrate contacting step, of immersing thecomposite material in boiling water. The immersing step may be usefulfor converting the deposition product into other oxidized silver species(such as silver oxides), thus potentially providing an opportunityfurther to “engineer” the composite material to provide desiredproperties of the deposition product. The immersing step may beperformed for any length of time, but preferably the immersing step isperformed for at least about 1 minute.

The composite material may be produced for many different applicationsincluding for electronics, materials engineering and medical purposes.The method according to the second aspect is particularly suited for theproduction of medical devices in circumstances where the metal is silverand the deposition product is comprised of an oxidized silver specieshaving the general formula Ag₇O₈X and optionally Ag₂SO₄ and/oroptionally one or more silver oxide compounds, due to the antimicrobialproperties exhibited by the deposition product and to the capability tocontrol the extent of the deposition of the deposition product on thesubstrate.

The term “medical device” as used herein means any article which has amedical application where antimicrobial properties may be desirable, andincludes all natural and synthetic materials and both fibrous andnon-fibrous materials. For example, the materials may be comprised of ametal, plastic, paper, glass, ceramic, textile, rubber, polymer,composite material or any other material or combination of materials.Non-limiting examples of medical devices which are encompassed by theinvention include wound dressings, splints, sutures, catheters,implants, tracheal tubes, orthopedic devices, drains, shunts,connectors, prosthetic devices, needles, medical instruments,laboratory, clinic and hospital equipment, furniture and furnishings,dental devices, as well as health care products such as personal hygieneproducts, sterile packaging, clothing, footwear etc.

Accordingly, the composite material may comprise a medical device or acomponent of a medical device and the term “medical device” as usedherein extends to both medical devices and components of medicaldevices.

In a preferred embodiment, the substrate is comprised of a wounddressing. The wound dressing may be comprised of any material orcombination of materials, including but not limited to metals, ceramics,glass, polymers, plastics, composite materials, natural materials,synthetic materials, synthetic textiles such as HDPE, rayon, nylon,polyacetates, polyacrylics and glass and natural textiles such ascellulose, wool, jute and cotton, whether in fibrous or non-fibrousform.

In a preferred embodiment of wound dressing, the wound dressing may becomprised of a polymer material such as high density polyethylene andmay be further comprised of an adhesive material comprising a skinadhesive layer. The skin adhesive layer may be comprised of across-linked silicon gel material. The wound dressing and/or thecross-linked silicon gel material may for example be comprised of aproduct sold under the Mepitel™ trade-mark or the Safetac™ trade-mark,both of which trade-marks are owned by Molnlycke Health Care AB ofSweden.

In one application, the deposition product may be selectively depositedon the skin adhesive layer and the production of the deposition productis preferably controlled so that the deposition product does notmaterially interfere with the adhesive properties of the skin adhesivelayer, yet still provides an acceptable antimicrobial effect withoutsignificant undesirable toxic effects. This result may be achieved bydepositing the deposition product on the skin adhesive layer such thatthe deposition product provides a desired antimicrobial effect but doesnot completely cover the surface of the skin adhesive layer. In thisapplication, preferably the amount of the deposition product which isdeposited on the substrate is such that the amount of total silver onthe substrate is selected to be between about 0.1 mg/cm² and about 1.0mg/cm², or more preferably between about 0.2 mg/cm² and about 0.6mg/cm², in order to achieve the desired result.

In other applications in which the deposition product is not depositedon an adhesive such as the skin adhesive layer, the amount of thedeposition product is preferably controlled to balance the desiredantimicrobial effect, undesirable toxic effects, and economicconsiderations.

In a third aspect, the invention is a medical device comprising acomposite material, wherein the composite material is comprised of asubstrate and a deposition product and wherein the deposition product iscomprised of an antimicrobially active oxidized silver speciescomprising a silver salt and a silver oxide.

The medical device according to the third aspect may be produced usingany of the methods of the invention. Preferably the medical device isproduced using a method according to the second aspect of the invention.

In certain preferred embodiments the invention provides methods fordepositing a deposition product comprising at least one oxidized silverspecies onto a substrate, thus producing a composite material. Since theoxidized silver species of the invention exhibit an antimicrobialactivity, composite materials comprising the oxidized silver species canbe used in various medical devices for prevention or inhibition ofinfections. These medical devices may include but are not limited towound dressings, adhesives, sutures, catheters and other articles whereantimicrobial properties are desirable.

The preferred embodiments of the invention may be used to producedeposition products and composite materials from aqueous solutions undera wide range of pH conditions, involving reactions in either acidic oralkaline solutions. The methods can be performed at, but are not limitedto, temperatures between about 2 degrees Celsius and about 60 degreesCelsius with about 10 degrees Celsius to about 40 degrees Celsius beingthe most preferable.

The method steps for certain preferred embodiments of the invention areas follows:

I. Under Acidic Conditions:

-   -   (a) immersing an article to be used as a medical device in an        aqueous/alcohol solution of NaOH for a sufficient time to        provide a reasonable etching and cleaning of the surface,        followed by washing of the article with distilled water until a        pH of 7 is attained, in order to remove residual alkali;    -   (b) immersing the article in an aqueous silver salt solution.        The aqueous silver salt solution may be prepared from any silver        salt which is soluble in water with the most preferred silver        salt being silver nitrate;    -   (c) adding a stoichiometrically suitable quantity of an        oxidizing agent to the mixed silver salt solution containing the        article. The oxidizing agent can be any oxidizing substance such        as persulfates, permanganates, hydrogen peroxide and the like,        with potassium persulfate (K₂S₂O₈) being the most preferred        oxidizing agent;    -   (d) adding a stoichiometrically suitable quantity of an acid to        the mixed silver salt solution containing the immersed article        in order to provide a source of anions. The acids that can be        used include any inorganic or organic acids including, but not        limited to carbonic acid, nitric acid, perchloric acid, sulfuric        acid, acetic acid, fluoroboric acid, phosphoric acid,        phosphorous acid, citric acid, acetylsalicylic acid and mixtures        thereof, but most preferably nitric acid, perchloric acid,        phosphoric acid, acetic acid or sulfuric acid;    -   (e) agitating the article in the mixed silver salt solution        comprising the soluble silver salt (preferably AgNO₃), the acid        (preferably nitric acid, perchloric acid, phosphoric acid,        acetic acid or sulfuric acid), and the oxidizing agent        (preferably potassium persulfate) at temperatures between 2        degrees Celsius and 30 degrees Celsius with temperatures between        10 degrees Celsius and 25 degrees Celsius being the most        preferred for between about 2 and 40 minutes until the article        is coated with a grayish, gray or black color;    -   (f) removing the article from the slurry and washing the article        with distilled water until a pH of 7 is achieved; and    -   (g) drying the article at room temperature.

Alternatively after step (e) the article may be immersed in boilingwater (about 90 degrees Celsius to about 100 degrees Celsius) for atleast 1 minute.

II. Under Alkaline Conditions:

-   -   (a) immersing an article to be used as a medical device in an        aqueous/alcohol solution of NaOH for a sufficient time to        provide a reasonable etching and cleaning of the surface;    -   (b) removing the article into a solution containing a silver        diamino complex in a concentration sufficient to adsorb the        silver ions at the surface of the article and for a duration of        about 2 minutes to about 5 minutes. The silver diamino complex        may be prepared by dissolving any silver salt or silver oxide in        ammonium hydroxide, and may be achieved by adding a        stoichiometrically suitable quantity of ammonium hydroxide to an        aqueous solution or suspension of the silver salt or silver        oxide until a clear colorless solution containing [Ag(NH₃)₂]⁺ is        obtained. The pH of this solution is usually in the range from        about 8 to about 12;    -   (c) removing the article without washing or rinsing into another        solution containing a strong alkali, most preferably NaOH or        KOH, and agitating the article in this solution until a clear        colorless solution is obtained and the article is clearly dyed        with a tan, gray, brown or black color, depending on the desired        amount of oxidized silver species. The time of contact of the        article with the alkaline solution may vary, depending on        temperature and silver ion concentration, but the most        preferable duration is about 1 minute to about 15 minutes at        room temperature or about 1 minute to about 10 minutes at a        temperature of between about 40 degrees Celsius and about 60        degrees Celsius;    -   (d) removing the dyed article from the solution and washing with        distilled water until a pH of 7 is achieved; and    -   (e) drying the article at room temperature.

Alternatively, in step (c), the method may involve, depending on theamount of silver required at the surface of the article, furtheradditions to the strong alkali solution of the silver diamino complexsolution and/or additions to the strong alkali solution of an oxidizingagent such as a persulfate, permanganate, peroxide or a mixture thereof,with potassium persulfate being the most preferred oxidizing agent.

BRIEF DESCRIPTION OF DRAWINGS

Embodiments of the invention will now be described with reference to theaccompanying drawings, in which:

FIG. 1 is an XRD pattern generated from a deposition product obtainedfrom the reaction of AgNO₃ and (NH₄)₂S₂O₈ according to Examples 15-16.

FIG. 2 is an SEM micrograph (magnification=2000×) generated from adeposition product obtained from the reaction of AgNO₃ and (NH₄)₂S₂O₈according to Examples 15-16.

FIG. 3 is an XRD pattern generated from a deposition product obtainedfrom the reaction of AgNO₃ and K₂S₂O₈ according to Examples 15-16.

FIG. 4 is an SEM micrograph (magnification=2000×) generated from adeposition product obtained from the reaction of AgNO₃ and K₂S₂O₈according to Examples 15-16.

FIG. 5( a) is an SEM micrograph (magnification=150×) generated from asample of uncoated HDPE mesh.

FIG. 5( b) is an SEM micrograph (magnification=1000×) generated from asample of HDPE mesh upon which a deposition product has been depositedaccording to Examples 15-16.

FIG. 6( a) is a photograph depicting a controlled zone of inhibition(CZOI) against Staphylococcus Aureus for a sample of HDPE mesh coatedwith a deposition product according to Examples 15-16.

FIG. 6( b) is a photograph depicting a controlled zone of inhibition(CZOI) against Pseudomonas Aeruginosa for a sample of HDPE mesh coatedwith a deposition product according to Examples 15-16.

FIG. 6( c) is a photograph depicting a controlled zone of inhibition(CZOI) against Candida Albicans for a sample of HDPE mesh coated with adeposition product according to Examples 15-16.

FIG. 7 is an SEM micrograph (magnification=30×) generated from asubstrate consisting of an uncoated sample of a perforated plasticcarrier material with a skin adhesive layer comprised of a hydrophobiccross-linked silicon gel (trade-mark Mepitel™).

FIG. 8 is an SEM micrograph (magnification=40×) generated from acomposite material consisting of a coated sample of a perforated plasticcarrier material with a skin adhesive layer comprised of a hydrophobiccross-linked silicon gel (trade-mark Mepitel™), in which a relativelysmall amount of deposition product has been deposited on the substratein accordance with the second and third aspects of the invention.

FIG. 9 is an SEM micrograph (magnification=2000×) generated from thecomposite material of FIG. 8, depicting the density and coverage of thedeposition product on the substrate.

FIG. 10 is an SEM micrograph (magnification=40×) generated from acomposite material consisting of a coated sample of a perforated plasticcarrier material with a skin adhesive layer comprised of a hydrophobiccross-linked silicon gel (trade-mark Mepitel™), in which a relativelylarger amount of deposition product (relative to FIG. 8 and FIG. 9) hasbeen deposited on the substrate in accordance with the second and thirdaspects of the invention.

FIG. 11 is an SEM micrograph (magnification=2000×) generated from thecomposite material of FIG. 10, depicting the density and coverage of thedeposition product on the substrate.

FIG. 12 is an XRD pattern generated from a substrate consisting of anuncoated sample of a perforated plastic carrier material with a skinadhesive layer comprised of a hydrophobic cross-linked silicon gel(trade-mark Mepitel™).

FIG. 13 is an XRD pattern generated from a composite material consistingof a coated sample of a perforated plastic carrier material with a skinadhesive layer comprised of a hydrophobic cross-linked silicon gel(trade-mark Mepitel™), in which a deposition product has been depositedon the substrate in accordance with the second and third aspects of theinvention.

FIG. 14 is a superimposition of the XRD patterns depicted in FIG. 12 andFIG. 13.

DETAILED DESCRIPTION

In preferred embodiments of the invention, antimicrobial properties ofmedical devices are achieved by the adsorption and deposition of adeposition product comprising an antimicrobially active silver specieswithin or at the surface of the medical device. These active silverspecies may include but are not limited at all oxidized silver speciessuch as silver salts, silver oxide (Ag₂O), higher silver oxides i.e.Ag(II) and Ag(III) (AgO, Ag₂O₃, Ag₃O₄ or like), silver oxy-salts with ageneral formula Ag₇O₈X where X can include one of acid anions such assulfates, chlorides, phosphates, carbonates, citrates, tartrates,oxalates and like. The deposition product may also contain someelemental silver deposited during the process.

The term “total silver” as used in herein is the total amount of silveras determined by a chemical analysis, which may include elemental(metallic) silver as well as silver originating from oxidized silverspecies.

The term “oxidized silver species” as used herein may involve but is notlimited at all compounds of silver where said silver is in +I, +II or+III valent states or any combinations thereof. These oxidized silverspecies include, for example silver (I) oxide, silver (II) oxide, silver(III) oxide or mixtures thereof, all silver salts having a solubilityproduct higher than 10⁻²⁰ (such as for example Ag₂SO₄, AgCl, Ag₂S₂O₈,Ag₂SO₃, Ag₂S₂O₃, Ag₃PO₄, and the like), and silver oxy-salts such asAg₇O₈X were X can include but is not limited at NO₃ ⁻, ClO₄ ⁻, SO₄ ²⁻,F⁻ etc.

The term “medical device materials” as used herein may include materialssuch as metals, ceramics, glass, polymers, plastics, compositematerials, a variety of natural materials, fabrics, textile made ofeither synthetic (HDPE, rayon, nylon, polyacetates, polyacrylics, glassetc.) or natural (cellulose, wool, jute, cotton, etc.) fibers.

The term “bacteriostatic activity”, as used herein relates to theinhibition of bacterial growth, but not to actually killing thebacteria. Successful treatment therefore requires the host's immunesystem to clear the pathogen. Treatment is compromised when theantimicrobial materials are stopped before the pathogen has beencompletely cleared.

The term “bactericidal activity” as used herein relates to killingbacteria with or without lysis of the target cell. These types ofantimicrobial materials are particularly advantageous inimmunosuppressed individuals. A disadvantage to bactericidal activity iscell lysis, which can release lipolysaccharides which are toxic to thehost. However, if the concentration of the said antimicrobial materialis relatively low so that toxic effects cannot occur, a combination ofboth bacteriostatic and bactericidal activities may be ideal forantimicrobial materials.

In the preferred embodiments, the deposition of the deposition productcomprising the oxidized silver species is accomplished by firstproviding an aqueous solution of monovalent silver salt or a silvercomplex such as silver nitrate, perchlorate or silver diamino complex,with silver nitrate being the most preferable if the reaction is carriedout under acidic conditions or at close to neutral conditions (i.e. atpH below 7), and with silver diamino complex, (i.e., [Ag(NH₃)₂]⁺) beingthe most preferable if the reaction is carried out under alkalineconditions (i.e. at pH above 7).

Prior to the production of the composite material comprising the articleas a substrate and the deposition product, the article is preferablyimmersed in an alkaline solution containing 50 vol. % ethanol and 50vol. % of an aqueous solution containing 30 g/L NaOH. Other cleaning andetching solutions can be used depending upon the material from which themedical device is made, upon the toxicity of the said cleaning oretching solutions, and upon the possibility that some toxic substancesmay adsorb at the surface of the article. Of course any use of toxic orcarcinogenic substances during the etching step should be avoided. Ifproduction of the deposition product is carried out under acidicconditions, the article is preferably washed with distilled water afterthe etching step until a pH of 7 is achieved in order to remove residualalkali remaining after the etching step.

When the reaction is carried out in the pH range below 7 (i.e., underacidic conditions), the clean pretreated article to be used as a medicaldevice containing oxidized silver species at the surface of the same issimply immersed into an agitated 1% AgNO₃ aqueous solution as adeposition solution. After exposure of the said article to thedeposition solution for a duration preferably of about 2 to about 10minutes, a solution of an oxidizing agent is added. Alternatively, theoxidizing agent may be added to the deposition solution before thearticle is immersed into the deposition solution, but this may result insome production of the deposition product before the article is presentin the deposition solution.

Although a wide range of oxidizing agents such as permanganates,persulfates, hydrogen peroxide, hypochlorites etc., may be used underspecific conditions and with the proper concentrations, the preferredoxidizing agent is a persulfate, more preferably either ammoniumpersulfate or potassium persulfate., and most preferably potassiumpersulfate The persulfate facilitates the precipitation and depositionof the deposition product on or within the article.

The concentration of persulfate in the deposition solution may be in arange from about 1 gram per liter to about 250 gram per liter with theconcentration of about 50 gram per liter being the most preferable.After agitation for about 2 minutes to about 5 minutes, the solution of1% AgNO₃ and persulfate may be acidified with an organic or inorganicacid such as HNO₃, HClO₄, H₂SO₄ or CH₃COOH such that the concentrationof the free acid preferably is about 9% HNO₃, 9% HClO₄ acid, 5% H₂SO₄,or 5% CH₃COOH. Although other acids may be used the most preferableacids are H₂SO₄, HClO₄ or HNO₃.

The agitation of the deposition solution is not strictly required, butin order to achieve a more uniform distribution of the depositionproduct and an efficient reaction yield, the agitation of the solutionis recommended. Agitation can be realized by many different ways such asfor example mechanical stirring, magnetic stirring or ultrasonicagitation.

Following addition of the persulfate (preferably potassium persulfate)to the deposition solution of 1% AgNO₃ within the time of about 1 minuteto about 10 minutes, and depending on the concentration of thepersulfate as well as on the conditions of agitation, the formationfirst of a yellow brown color of the solution and then a black grayishprecipitate will occur. This brown color of the solution is attributedto the oxidation of Ag(I) to Ag(II).

The black grayish deposit at the article or in the bulk solution is aconsequence of the formation of silver oxy-salts such as Ag₇O₈X, were Xis an anion, depending on the acid used in the method e.g. HNO₃ (NO₃—),H₂SO₄ (SO₄ 2), etc. The decomposition of the silver oxy-salts may bepresented as:Ag(Ag₃O₄)₂X=AgX+AgO  (1)

Persulfates are powerful oxidizing agents. They can therefore be reducedin aqueous solutions according to the following reactions:S₂O₈ ²⁻+2e ⁻=2SO₄ ²⁻, with E°=1.96 V  (2)S₂O₈ ²⁻+2H⁺+2e ⁻=2HSO₄ ⁻, with E°=1.96 V  (3)andS₂O₈ ²⁻+2H₂O=2H⁺+2SO₄ ²⁻+H₂O₂, with ΔG°=−36 kJ/mol  (4)

A consequence of the reduction of persulfate is the oxidation of Ag(I)to Ag(II) and Ag(III), probably according to the following reactions:Ag⁺=Ag²⁺⁺ e ⁻, with E°=1.98 V  (5)Ag⁺+H₂O=AgO⁺+2H⁺ +e ⁻, with E°=1.998 V  (6)Ag²⁺+H₂O=AgO⁺+2H⁺ +e ⁻, with E°=2.06 V  (7)Ag⁺+H₂O=AgO+2H⁺ +e ⁻, with E°=1.772 V  (8)

In this way the composite material comprising the article to be used asa medical device and the deposition product may include a combination ofoxidized silver species i.e. Ag(I)- and Ag(II)-oxides as well as silversalts such as nitrates, persulfates, sulfates, phosphates, perchloratesand like, silver salts of a general formula Ag₇O₈X and perhaps traces ofpure elemental silver. After production of the composite material, thearticle is removed from the deposition solution and then preferablywashed with distilled water until a pH of 7 is achieved. When thewashing is completed, the medical device comprising the compositematerial may be dried at room temperature and packaged.

When the reaction is carried out in the pH range above 7 (i.e., underalkaline conditions) the article to be used as a medical device is firstimmersed in an etching solution comprising an alkaline solutioncontaining alcohol. The most preferable solution according to thisinvention is either NaOH or KOH with concentrations 15 to 40 g/L. Thealcohol used in this solution may be ethyl alcohol, methyl alcohol ormixtures therein in a concentration above 50 vol. %. The immersion ofthe article into the etching solution is carried out in order to etchand clean the surface of the article to provide a reasonable adhesion ofthe deposition product comprising an oxidized silver species which isdeposited on or within the article thereafter. The immersion time of thearticle is preferably in the range of between about 5 minutes and about20 minutes, with about 10 minutes being the most preferable.

After the exposure to the alkali/alcohol solution for about 10 minutes,the article is then removed without washing or rinsing into a firstbasic environment comprising a first basic solution containing silverdiamino complex i.e. [Ag(NH₃)₂]⁺ in a concentration sufficient to adsorbsilver ions at the surface of the article and for a duration of about 2minutes to about 5 minutes. The silver diamino complex is preferablyprepared from a silver salt or silver oxide dissolved or suspended inwater by a dissolution with NH₄OH (28 vol. %).

Consequently, the first basic solution is prepared in a way such that asolution of any silver salt (such as for example AgNO₃ or AgClO₄) or anysilver oxide (such as Ag₂O or Ag₂O₂ or AgO) or any silver salt suspendedin water (such as AgCl, Ag₂CO₃, Ag₂SO₄ or the like), the ammoniumhydroxide is added in a stoichiometrically suitable concentration sothat a clear colorless solution is obtained. The concentration of silverion in this silver diamino complex solution, as calculated for Ag⁺ ioncan vary from 1 to 20 g/L with about 10 g/L being the most preferable.The pH of the first basic solution is usually between about 8 and about12 with the most preferred pH being in the range of between about 10 andabout 11.

After exposure of the article to the first basic solution for about 2minutes to about 5 minutes, the article is removed without washing orrinsing into a second basic environment comprising a second basicsolution containing a strong alkali, most preferably NaOH or KOH. Thearticle is kept in this solution under agitation until a clear colorlesssolution is obtained and the article is dyed with a tan, gray, brown orblack color, depending on the desired amount of oxidized species to bedeposited at or within the surface of the article. The time of contactof the article with the second basic solution may vary depending ontemperature and the silver ion concentration, but most preferable timeis about 1 minute to about 15 minutes at room temperature or about 1minute to about 10 minutes at a temperature of between about 40 degreesCelsius and about 60 degrees Celsius.

Alternatively, the method may involve an addition of an oxidizing agentto the second basic solution, preferably a persulfate, more preferablyeither ammonium persulfate or potassium persulfate, and most preferablypotassium persulfate. The oxidizing agent may be added directly to thesecond basic solution containing the article. In addition, depending onthe amount of silver desired to be deposited as the deposition product,addition of a residual silver compound such as the silver diaminocomplex [Ag(NH₃)₂]⁺ may also be beneficial.

Upon immersion of the article, previously exposed to the first basicsolution, into the second basic solution, the following reaction at thesurface of the article may occur:2Ag(NH₃)₂NO₃+2NaOH=Ag₂O+4NH₃+H₂O+2NaNO₃  (9)

In this way, at the surface of the article, Ag₂O will deposit as theresult of the reaction (9). The addition of an oxidizing agent such asammonium persulfate (i.e., (NH₄)₃S₂O₈) to the second basic solution mayresult in the oxidation of silver ions and the reduction of S₂O₈ ²⁻ ionspursuant to the following reactions:Ag⁺=Ag²⁺ +e ⁻, with E°=1.96 V  (10)andS₂O₈ ²⁻+2e=2SO₄ ²⁻, with E°=1.96 V  (11)

The reactions of Ag(NH₃)₂ ⁺ ion with ammonium persulfate can berepresented as follows:Ag(NH₃)₂NO₃+(NH₄)₂S₂O₈=Ag₂S₂O₈+2NH₄NO₃+4NH₃  (12)Ag₂S₂O₈+H₂O=2AgO+2H₂SO₄  (13)Ag(NH₃)₂NO₃+(NH₄)₂S₂O₈+2H₂O=2NH₄NO₃+2AgO+2H₂SO₄+4NH₃  (14)orAg(NH₃)₂NO₃+(NH₄)₂S₂O₈+2H₂O=2NH₄NO₃+2AgO+2(NH₄)₂SO₄  (15)

In this way, the deposition product may contain Ag₂O, AgO or otherhigher oxides of silver Ag(II), Ag(III) and mixtures therein. Also, ifalcohol is present in the reacting solution, due to transferring fromthe etching solution some elemental silver may occur in the depositionproduct. This is because in the presence of persulfates, alcohols can beoxidized to aldehydes according to the reactions:CH₃OH═H₂CO+2H⁺+2e ⁻  (16)C₂H₅OH═CH₃CHO+2H⁺+2e ⁻  (17)

Under the alkaline conditions, the aldehydes can reduce the silver ionsto the elemental silver according to the reaction:2Ag(NH₃)₂OH+HCHO=2Ag+4NH₃+HCOOH+H₂O  (18)

After production of the composite material comprising the article andthe deposition product comprising the oxidized silver species iscompleted, the article is removed, carefully washed with water until apH of 7 is achieved. The article may then be dried at room temperatureand packaged.

Following are examples which illustrate the present invention.

EXAMPLES Example 1

Nine (9) pieces of high density polyethylene mesh (HDPE), withdimensions 10×8 cm each, were immersed in 100 ml of an etching solutioncontaining 50 mL alcohol (95% C₂H₅OH and 5% CH₃OH) and 50 mL of 28 g/LNaOH solution for 5 minutes. After 5 minutes of etching the H DPE meshwas transferred without washing or rinsing into 40 mL of an Ag⁺solution, containing 15.3 g/L AgNO₃ and a stoichiometrically suitablevolume of NH₄OH (28 vol. %). The HDPE mesh was kept in this solution for2 minutes. After 2 minutes of exposure to the ammoniacal Ag(NH₃)₂ ⁺solution, the HDPE mesh was transferred without washing or rinsing into150 mL of a 28 g/L NaOH solution stirred with a magnetic stirrer. Assoon as the HDPE mesh was immersed into NaOH solution, the formation ofa precipitate yellowish-brown in color occurred. Under agitation aresidual silver compound (about 38 mL of the Ag(I) solution) was addedand after that 5 mL of a 250 g/L (NH₄)₂S₂O₈ solution was added.Agitation was continued for 10 minutes. During this time thesolution/precipitate became black. The HDPE mesh was uniformly coatedand was black and shiny in appearance. The coated HDPE mesh was thenremoved from the solution and carefully washed with distilled wateruntil pH 7.00, and dried at room temperature. After drying, the mesh wasa black and shiny in appearance.

Chemical analysis determined that the HDPE mesh coated with oxidizedsilver species contained about 0.08 mg total silver per cm² of mesh. Thecoated mesh was further analyzed by XRD analysis. As found by the XRDanalysis the mesh included Ag₂O, Ag(II) oxides, Ag₇O₈NO₃ and some tracesof the elemental silver. Both bacteriostatic and bactericidal activitiesof silver coated HDPE substrates were tested against PseudomonasAeruginosa and Staphylococcus Aureus. One hour bactericidal activitytests of coated HDPE mesh against both Pseudomonas Aeruginosa andStaphylococcus Aureus were positive. The bacteriostatic activity wasalso tested. The controlled zone of inhibition surrounding the testsample, where no bacteria growth occurred, was estimated at about 9 mmto about 10 mm.

Example 2

Samples of HDPE mesh with dimensions 10×8 cm were immersed in 100 mL ofan etching solution containing 50 mL of 28 g/L NaOH and 50 mL ofdenatured ethanol (95% C₂H₅OH and 5% CH₃OH) for 5 minutes. After 5minutes of etching the HDPE mesh was transferred without washing orrinsing into 40 mL of an ammoniacal Ag(I) solution containing 15.3 g/LAgNO₃ and a stoichiometrically suitable quantity of NH₄OH (28 vol. %).The HDPE mesh was kept in this solution for 2 minutes. The HDPE mesh wasthen transferred without washing or rinsing into 150 mL of a solutioncontaining 28 g/L NaOH. The NaOH solution immediately became brown. Uponaddition of a residual silver compound (about 38 mL of the Ag(I)solution) the solution turned to a dark brown color and with a continuedagitation for about 5 minutes the solution became black. When theagitation was stopped, the black precipitate occurred in the bulksolution as a result of its separation from the HDPE mesh material.After washing and rinsing with distilled water the mesh appeared to belight tan or at the most slightly gray as a consequence of the coatingwith silver compounds.

The amount of total silver deposited on the HDPE mesh as determined bychemical analysis was estimated at about 0.04 mg/cm². Antimicrobialactivities (bactericidal and bacteriostatic) were tested againstPseudomonas Aeruginosa and Staphylococcus Aureus. One hour bactericidalactivity of the coated HDPE mesh was positive. The bacteriostaticactivity, as estimated according to the controlled zone of inhibition(CZOI) for the bacterial growth was also positive. The CZOI wasestimated at about 4 mm.

Example 3

Samples of HDPE mesh were immersed in an etching solution containing 100mL of 28 g/L NaOH solution for 5 minutes. The mesh was then transferredwithout washing or rinsing into 40 mL of an ammoniacal Ag(I) solutioncontaining 15.3 g/L AgNO₃ and a stoichiometrically suitable volume ofNH₄OH (28%). After 2 minutes of immersion, the mesh was transferredwithout washing or rinsing into 150 mL of a 28 g/L NaOH solution stirredmagnetically. The solution became immediately brown due to formation ofa precipitate. Addition of a residual silver compound (about 38 mL ofthe Ag(I) solution) resulted in the formation of a dark brownprecipitate. The color of the solution did not change further even after30 minutes of mixing at room temperature. The HDPE mesh was then washedand rinsed very carefully with distilled water. The color of the HDPEmesh did not change significantly, but some change in color from whiteto a light tan appeared.

The amount of total silver deposited on the HDPE mesh was estimated atabout 0.02 mg/cm². The antimicrobial activities (both bacteriostatic andbactericidal) of these samples were tested against PseudomonasAeruginosa and Staphylococcus Aureus. The results showed a positivebactericidal activity and the CZOI was estimated at about 3 mm.

Example 4

Samples of HDPE mesh were immersed in 100 mL of a solution containing 1g AgNO₃ and 1 mL of 67% HNO₃ as a source of anions. After 5 minutes ofimmersion, 5 g of (NH₄)₂S₂O₈ dissolved in 20 mL of water was added. Thesample was left for 30 minutes at room temperature, during which thesolution was stirred occasionally with a glass rod. During this time thesolution changed color from colorless to a dark brown and a formation ofa light gray precipitate in the bulk solution appeared. After 30minutes, the HDPE mesh was removed from the solution and carefullywashed with distilled water. The washed HDPE mesh had a gray color. Thecoating was uniformly distributed at the surface of this material.

The amount of total silver deposited on the HDPE mesh was estimated at0.09 mg/cm². The bactericidal activity for these samples was positive.The CZOI was estimated at about 8 mm.

Example 5

HDPE mesh was coated with silver oxidized compounds using a methodsimilar to that described in Example 4, with a few differences asoutlined in the description that follows.

Samples of HDPE mesh were immersed in 100 mL of a solution containing 10g/L AgNO₃ and 15 mL/L HNO₃ (67%) as a source of anions. To this solution10 mL of 500 g/L (NH₄)₂S₂O₈ was added. The solution was magneticallystirred. After 7 minutes of stirring the solution became yellow-brownand formation of a very small amount of precipitate occurred. Thestirring was continued for the next 30 minutes. After 30 minutes, theHDPE mesh was removed from the slurry and carefully washed withdistilled water. The washed HDPE mesh had a gray color. The coating wasuniformly distributed at the surface of the HDPE mesh.

The amount of total silver deposited on the HDPE mesh was estimated at0.08 mg/cm². The bactericidal activities against Pseudomonas Aeruginosaand Staphylococcus Aureus were positive. The CZOI was estimated at about7 mm.

Example 6

HDPE mesh was coated with silver oxidized compounds using a methodsimilar to that described in Example 4 and Example 5, with a fewdifferences as outlined in the description that follows.

Samples of HDPE mesh were immersed in 100 mL of a solution containing 10g/L AgNO₃ and 15 mL/L HNO₃ (67%) as a source of anions. To this solution10 mL of 500 g/L (NH₄)₂S₂O₈ was added. The solution was agitatedultrasonically. After 2 minutes of stirring the solution becameyellow-brown and formation of a very small amount of precipitateoccurred. The stirring was continued for the next 30 minutes. After 30minutes, the HDPE mesh was removed from the solution and carefullywashed with distilled water. The washed HDPE mesh had a gray color. Thecoating was uniformly distributed at the surface of the HDPE mesh.

The amount of total silver deposited on the HDPE mesh was estimated at0.08 mg/cm². The bactericidal activities against Pseudomonas Aeruginosaand Staphylococcus Aureus were positive. The CZOI was estimated at about7 mm.

Examples 7-9

In these examples the effect of different acids (i.e., sources ofanions) is clearly shown for coating of HDPE mesh with oxidized silverspecies under acidic conditions. In Example 4, HNO₃ was used as a sourceof anions to supplement the anions contained in the AgNO₃, while inExamples 7-9 perchloric acid (HClO₄), sulfuric acid (H₂SO₄) and aceticacid (CH₃COOH) respectively were used as a source of anions.

Samples of HDPE mesh were immersed in 100 mL of a solution containing 1g AgNO₃. To this solution 1 mL of HClO₄ (70%) (Example 7), 0.5 mL ofH₂SO₄ (98%) (Example 8) and 15 mL of CH₃COOH (5%) (Example 9) wereadded. After 2 minutes of the exposure of HDPE mesh to these solutions,20 mL of 250 g/L (NH₄)₂S₂O₈ was added. The mixing was continued for thenext 30 minutes. In the solutions containing HClO₄ (Example 7) and H₂SO₄(Example 8) formation of a black grayish precipitate occurred similar toExample 4. When the precipitate settled the solutions were clear andyellow-brown in color. The yellow-brown color suggests the presence ofAg(II) complexes in the solution. The coated HDPE mesh was then removedfrom the slurry and carefully washed and rinsed with distilled water andthereafter dried at room temperature. After drying the HDPE mesh coatedin the presence of 1 mL of HClO₄ (70%) (Example 7), or in the presenceof 0.5 mL of H₂SO₄ (98%) (Example 8) appeared to be grayish in color.However, the HDPE mesh coated in the presence of 15 mL of CH₃COOH (5%)(Example 9) was white and it did not change its color.

The coated HDPE mesh (Examples 7-9) were analyzed for the total silvercontent, and the antimicrobial activity was also evaluated againstPseudomonas Aeruginosa and Staphylococcus Aureus. The amount of totalsilver deposited on the HDPE mesh was estimated at 0.08 mg/cm² (forsamples coated in the presence of HClO₄), 0.07 mg/cm² (for samplescoated in the presence of H₂SO₄) and 0.01 mg/cm² (for the samples coatedin the presence of CH₃COOH). The bactericidal activities againstPseudomonas Aeruginosa and Staphylococcus Aureus were positive. The CZOIwas estimated at about 6 mm (for samples coated in the presence of HClO₄or H₂SO₄) and about 1 to 2 mm (for samples coated in the presence ofCH₃COOH).

Example 10

Samples of HDPE mesh with dimensions 10×8 cm were immersed in 100 mL ofan etching solution containing 50 mL of 28 g/L NaOH and 50 mL ofdenatured ethanol (95% C₂H₅OH and 5% CH₃OH) for 5 minutes. After 5minutes of etching the HDPE mesh was transferred without washing orrinsing into 40 mL of an ammoniacal Ag(I) solution containing 15.3 g/LAgNO₃ and a stoichiometrically suitable quantity of NH₄OH (28 vol. %).The HDPE mesh was kept in this solution for 2 minutes. The HDPE mesh wasthen transferred without washing or rinsing into 150 mL of a solutioncontaining 28 g/L NaOH. The NaOH solution immediately became brown.After mixing for 2 minutes, the solution became clear and colorless andthe mesh was tan in color. When the agitation was stopped, the HDPE meshwas removed from solution and washed with distilled water. After washingand rinsing the mesh appeared to be tan in color as a consequence of thecoating with silver compounds.

The coated HDPE mesh was analyzed for silver content and forantimicrobial activity against Pseudomonas Aeruginosa and StaphylococcusAureus. These samples contained between 0.04 and 0.08 mg/cm² totalsilver. The bactericidal activities against Pseudomonas Aeruginosa andStaphylococcus Aureus were positive. The CZOI was estimated at about 10mm.

Example 11

A patterned wound dressing made of a perforated plastic carrier materialwith a skin adhesive layer comprised of a hydrophobic cross-linkedsilicon gel (trade-mark Mepitel™, product of Molnlycke Health Care AB,Sweden), dimensions 8×15 cm was exposed to a solution containing 15 g/LNaOH at room temperature for 5 minutes. Under conditions of agitation 40mL of a solution containing 15.3 g/L AgNO₃ and a proper volume of NH₄OH(28 vol. %) was added. The wound dressing was kept in this solution andagitated for the next 5 minutes. The wound dressing was then removedfrom the solution and carefully washed with distilled water. Drops ofwater were removed with a soft paper and the wound dressing was dried atroom temperature.

The coated wound dressing was analyzed for antimicrobial activityagainst Pseudomonas Aeruginosa and Staphylococcus Aureus. MH plates andTryptic Soy Broth were used for analysis. Pseudomonas Aeruginosastandard was set to 0.5 McFarland standard. One hour of bactericidalactivity of the coated wound dressing against the bacteria where TSBbroths were incubated for 24 hours was positive. The controlled zones ofinhibition (CZOI), for the bacterial growth (bacteriostatic activity)were above 8 mm. The same samples of coated wound dressing were testedfor seven days for antimicrobial activity. The values of CZOI after 2days were 20.5 mm, after 3 days 19 mm, after 4 days 20.5 mm, after 5days 19 mm and after 7 days 7 mm. These results show very goodresistance towards bacteria for a relatively long time (7 days).

Example 12

A patterned wound dressing made of a perforated plastic carrier materialwith a skin adhesive layer comprised of a hydrophobic cross-linkedsilicon gel (trade-mark Mepitel™, product of Mölnlycke Health Care AB,Sweden), dimensions 8×15 cm was exposed to 500 mL of a 1% AgNO₃solution. To this solution was added 200 mL of a solution containing 20g K₂S₂O₈ and mixing was continuous for the next 20 minutes. The wounddressing was then removed from the solution and carefully washed withdistilled water. Drops of water were removed with soft paper and thewound dressing was dried at room temperature.

The coated wound dressing contained 0.25-0.55 mg/cm² of total silver.The coated wound dressing was then analyzed for antimicrobial activityin the same manner as described in Example 11. The results showedexcellent antimicrobial activity for 7 days.

Example 13

A patterned wound dressing made of a perforated plastic carrier materialwith a skin adhesive layer comprised of a hydrophobic cross-linkedsilicon gel (trade-mark Mepitel™, product of Mölnlycke Health Care AB,Sweden), dimensions 8×15 cm was coated in a way as described in Example12, except that (NH₄)₂ S₂O₈ was used as an oxidizing agent instead ofK₂S₂O₈, in the same amount and in the same manner as described inExample 12.

The coated wound dressing produced as described in this example wasanalyzed for the antimicrobial activity. The results showed excellentantimicrobial activity.

Example 14

A slurry was prepared by mixing 500 mL of a 1% AgNO₃ solution and 200 mLof an aqueous solution containing 20 g K₂S₂O₈ for 10 minutes. To thisslurry a patterned wound dressing made of a perforated plastic carriermaterial with a skin adhesive layer comprised of a hydrophobiccross-linked silicon gel (trade-mark Mepitel™, product of MölnlyckeHealth Care AB, Sweden), dimensions of 8×15 cm was added and mixing wascontinued for the next 20 minutes. The coated wound dressing was thenremoved from the slurry, carefully washed with water then dried asdescribed in the Example 12. The coated wound dressing was black-greyishin appearance.

The antimicrobial activity of the coated wound dressing was tested in away described in Example 11. The results showed excellent antimicrobialactivity for seven days.

Examples 15-16

All method steps were performed at room temperature (22 degrees Celsius±2 degrees Celsius), unless otherwise specified.

Samples of HDPE mesh were coated with oxidized silver species asfollows. HDPE mesh with dimensions 10×10 cm were immersed into 100 mL ofa 1% AgNO₃ solution and thoroughly wetted. After the exposure of theHDPE mesh to the solution for 10 minutes, 20 mL of a solution containingeither 250 g/L of (NH₄)₂S₂O₈ or 250 g/L of K₂S₂O₈ was added undermagnetic stirring. The mixing was continued for the next 15 minutes. Thecoated HDPE mesh was then removed from the slurry and was observed to begrayish-black in appearance. After coating, the HDPE mesh was washedwith water and then dried.

The bacteriostatic activity for the controlled zone of inhibition (CZOI)of bacterial or fungal growth was tested against Pseudomonas Aeruginosa,Staphylococcus Aureus or Candida Albicans, using standard procedures asdescribed in the literature.

Discussion of Examples 15-16

(a) Deposition of Silver Deposition Products Using (NH₄)₂S₂O₈

Upon addition of ammonium persulfate to the AgNO₃ solution, a gradualcolor change from colorless through yellow, brown and finally to a cloudsolution containing grayish-black precipitate was observed. Time for theappearance of the grayish-black precipitate at room temperature wasestimated at 5 to 10 minutes. It was noted that if the reaction takesplace at temperatures above 30 degrees Celsius, the precipitation andcolor change do not occur.

Persulfates are powerful oxidizing agents. In aqueous solutionspersulfates can be reduced to sulfates (S. I. Zhdanov, Sulfur, Selenium,Tellurium and Polonium, in Standard Potentials in Aqueous Solutions, A.J. Bard, R. Parsons and J. Jordan Editors, Marcel Dekker Inc., New York(1985)). A consequence of the reduction of persulfate is the oxidationof Ag(I) to Ag(II) and Ag(II) to Ag(III). The grayish-black precipitatedeposited on the HDPE mesh was formed as a result of the reduction ofpersulfate and a consequent oxidation of Ag(I) ions.

During precipitation of the deposition product, the pH of the solutiondropped from about 2 to below 1. The decrease in pH of the solution wasmore significant when K₂S₂O₈ is used as an oxidizing agent instead of(NH₄)₂S₂O₈, in that a decrease in pH from about 7 to below 1 wasobserved.

(b) Properties of Deposition Products Produced Using (NH₄)₂S₂O₈

The grayish-black precipitate itself represents a mixture of silverargentic nitrate Ag(Ag₃O₄)₂NO₃

Ag₇NO₁, and Ag₂SO₄. Indeed, as found by XRD analysis, the peaks in thepatterns showed a reasonable match for Ag₂SO₄ and Ag₇O₈NO₃ (FIG. 1). Itis apparent that the oxidation of AgNO₃ with (NH₄)₂S₂O₈ leads to theprecipitation of silver oxy-salt Ag₇NO₁₁, and also Ag₂SO₄. Theprecipitation of Ag₂SO₄ is usually not observed when K₂S₂O₈ is used asan oxidizing agent of Ag(I) ions (see the discussion below relating tooxidation with K₂S₂O₈).

FIG. 2 provides a SEM micrograph of the grayish black precipitate. Thesmaller “cubical” particles represent Ag₇O₈NO₃ and their size, based onSEM is estimated at about 2.5 μm. The shape of these particles was foundto be in very good agreement with the results of Skanavi-Grigoreva (M.S. Skanavi-Grigoreva, I. L. Shimanovich, Zh. Obsh., Khim., 24, 1490(1954)). who produced this material by the electrolysis of an aqueousAgNO₃ solution. The larger, cylindrical particles represent silversulfate (Ag₂S₂O₄).

(c) Deposition of Silver Deposition Products Using K₂S₂O₈

Some differences in the formation of the grayish-black precipitate wereobserved when K₂S₂O₈ was used instead of (NH₄)₂S₂O₈, as the oxidizingagent of Ag(I). The precipitation of the grayish-black compound wassignificantly faster, and occurred within 1 minute upon addition ofK₂S₂O₈ to the AgNO₃ solution. During this time, the pH of the solutionchanged from the initial pH of about 7 to below 1 after theprecipitation.

(d) Properties of Deposition Products Produced Using K₂S₂O₈

As determined by XRD analysis in FIG. 3, all the peaks in the patternexactly match the compound of composition Ag₇O₈NO₃. No other compoundswere identified in this XRD pattern.

The theoretical amount of Ag in the compound Ag₇O₈NO₃ is 79.90%. Thechemical analysis determined that the grayish black precipitatecontained about 78.80% Ag. This result shows a good agreement of theexperiments with the theory.

The SEM micrographs of the powder produced by the chemical oxidation ofAgNO₃ with K₂S₂O₈ are presented in FIG. 4. It appears that the particlesare uniform and cubical in their shape. The size of these particles isestimated at about 2.5 μm.

(e) Antimicrobial Activity

The comparison of the SEM micrographs of uncoated and coated HDPE meshsamples is presented in FIG. 5. As shown in FIG. 5, the surface of theHDPE is partially covered with the Ag(Ag₃O₄)₂NO₃ particulates.

These samples were tested for bioactivity against the bacteriaPseudomonas Aeruginosa, Staphylococcus Aureus or fungi Candida Albicans.As can be seen from the photographs presented in FIG. 6, clear zonessurrounding the test samples (where a growth of tested microorganismsdid not occur) were observed in all cases for Staphylococcus Aureus (agram-positive bacteria), Pseudomonas Aeuguginosa (a gram-negativebacteria) and Candida Albicans (an example of fungi). The size of thecontrolled zone of inhibition (CZOI), where the growth of testedmicroorganisms was not observed, was estimated at 3 mm to 5 mm for alltested samples. These results suggest that the deposition products haveantibacterial and antifungal properties. Furthermore these results arein agreement with previously published results, where was suggested thatonly oxidized silver species, but not metallic silver exhibit anantimicrobial activity.

(f) Conclusions Relating to Examples 15-16

It has been demonstrated that deposition products, namely those ofcomposition Ag₇NO₁₁×3Ag₂SO₄ or Ag₇NO₁, can successfully be deposited aspowders or on a substrate such as HDPE mesh, by a simple reactionbetween AgNO₃ and (NH₄)S₂O₈ or K₂S₂O₈. These compounds are soluble inboth concentrated HNO₃ or NH₄OH.

Example 17

Samples of a substrate consisting of a patterned wound dressing made ofa perforated plastic carrier material with a skin adhesive layercomprised of a hydrophobic cross-linked silicon gel (trade-markMepitel™, product of Molnlycke Health Care AB, Sweden) were subjected toSEM micrography to observe the density and coverage on the substrate ofa deposition product deposited on the substrate in accordance with thesecond and third aspects of the invention, and to XRD analysis toanalyze the composition of the deposition product deposited on thesubstrate.

FIG. 7 depicts an uncoated sample of the Mepitel™ wound dressing at amagnification of 30×. FIGS. 8-11 depict samples of composite materialswhich have been produced according to the second and third aspects ofthe invention in the same manner as described in Example 14.

FIG. 8 depicts a composite material comprising a coated sample of theMepitel™ wound dressing at a magnification of 40×, in which a relativelylow amount of deposition product has been deposited on the substrate.FIG. 9 depicts the composite material of FIG. 8 at a magnification of2000×, and clearly shows that the density and coverage of the depositionproduct is such that the skin adhesive layer of the Mepitel™ wounddressing is relatively unobstructed by the deposition product.

FIG. 10 depicts a composite material comprising a coated sample of theMepitel™ wound dressing at a magnification of 40×, in which a higheramount of deposition product has been deposited on the substrate incomparison with FIG. 8 and FIG. 9. FIG. 11 depicts the compositematerial of FIG. 10 at a magnification of 2000×, and clearly shows thatthe skin adhesive layer remains relatively unobstructed by thedeposition product.

FIG. 12 depicts an XRD pattern for an uncoated sample of the Mepitel™wound dressing. FIG. 13 depicts an XRD pattern for a composite materialcomprising a sample of the Mepitel™ wound dressing which has been coatedwith a deposition product according to the second and third aspects ofthe invention in the same manner as described in Example 14. FIG. 14superimposes the XRD patterns from FIG. 12 and FIG. 13.

Referring to FIG. 14, the peaks which are observed in the pattern fromFIG. 13 but which are not observed in the pattern from FIG. 12 may beattributed to the deposition product. These peaks define the depositionproduct as comprising at least some amount of Ag₇O₈NO₃.

Example 18

Samples of a substrate consisting of a patterned wound dressing made ofa perforated plastic carrier material with a skin adhesive layercomprised of a hydrophobic cross-linked silicon gel (trade-markMepitel™, product of Molnlycke Health Care AB, Sweden) coated with 0.6mg/cm² of total silver according to the second and third aspects of theinvention in the same manner as described in Example 14 were exposed toa solution containing 10 g/L Na₂S. After 10 minutes of exposure to theNa₂S solution the coated wound dressing samples were carefully washedwith water until pH 7.

After drying, the samples were tested for antimicrobial activity againstPseudomonas Aeruginosa and Staphylococcus Aureus using standardprocedures. Clear zones of inhibition of bacterial growth surroundingtest samples were observed for both Pseudomonas Aeruginosa andStaphylococcus Aureus, suggesting that a deposition product producedaccording to the second and third aspects of the invention will exhibitan antimicrobial activity even after exposure to a sulfide containingenvironment.

1. A composite material comprising a substrate and a deposition product,wherein the substrate is a medical device selected from a group ofmedical devices consisting of a wound dressing, a splint, a suture, acatheter, an implant, a tracheal tube, a drain, a shunt, a needle and anadhesive, and wherein the deposition product consists essentially of atleast one oxidized silver species, and wherein the deposition product iscomprised of a compound having the formula Ag₇O₈X, where X s an anion.2. The composite material as claimed in claim 1 wherein the depositionproduct is further comprised of Ag₂SO₄.
 3. The composite material asclaimed in claim 1 wherein the deposition product is further comprisedof at least one silver oxide selected from the group of silver oxidesconsisting of monovalent silver oxide, bivalent silver oxide, trivalentsilver oxide and mixtures thereof.
 4. The composite material as claimedin claim 1 wherein X is derived from an acid.
 5. The composite materialas claimed in claim 1 wherein the deposition product is comprised of aplurality of oxidized silver species having a plurality of valent statesof silver.
 6. The composite material as claimed in claim 1 wherein X isselected from the group of anions consisting of HCO₃ ⁻, CO₃ ²⁻, NO₃ ⁻,ClO₄ ⁻, SO₄ ²⁻, F⁻, and mixtures thereof.
 7. The composite material asclaimed in claim 6 wherein X is comprised of NO₃ ⁻.
 8. The compositematerial as claimed in claim 1 wherein the medical device is a wounddressing.
 9. The composite material as claimed in claim 8 wherein thewound dressing is comprised of a high density polyethylene material. 10.The composite material as claimed, in claim 8 wherein the wound dressingis comprised of a cross-linked silicon gel.
 11. The composite materialas claimed in claim 8 wherein the wound dressing is comprised of a skinadhesive layer, wherein the skin adhesive layer is comprised of across-linked silicon gel, and wherein the deposition product isdeposited on the skin adhesive layer.
 12. The composite material asclaimed in claim 11 wherein the deposition product is further comprisedof Ag₂SO₄.
 13. The composite material as claimed in claim 11 wherein thedeposition product is further comprised of at least one silver oxideselected from the group of silver oxides consisting of monovalent silveroxide, bivalent silver oxide, trivalent silver oxide and mixturesthereof.
 14. The composite material as claimed in claim 11 wherein X isderived from an acid.
 15. The composite material as claimed in claim 11wherein the deposition product is comprised of a plurality of oxidizedsilver species having a plurality of valent states of silver.
 16. Thecomposite material as claimed in claim 11 wherein X is selected from thegroup of anions consisting of HCO₃ ⁻, CO₃ ²⁻, NO₃ ⁻, ClO₄ ⁻, SO₄ ²⁻, F⁻,and mixtures thereof.
 17. The composite material as claimed in claim 16wherein X is comprised of NO₃ ⁻.
 18. The composite material as claimedin claim 11 wherein the skin adhesive layer has adhesive properties andwherein the deposition product does not materially interfere with theadhesive properties of the skin adhesive layer.